Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The threonine (Thr) for alanine (Ala) codon 54 polymorphism of the fatty acid binding protein (FABP) 2 gene, when compared to the wild type, is associated with dyslipidemia. Since dyslipidemia is common in diabetes and is associated with increased cardiovascular risk, we tested the hypothesis that Thr-54 is associated with increased cardiovascular risk in patients with diabetes. The secondary prevention veterans affairs HDL intervention trial (VA-HIT) was carried out in patients with dyslipidemia. The DNA of trial participants (n=776) was screened for the Thr-54 polymorphism and cardiovascular endpoints were monitored. The polymorphism was detected in 370 (47.7%). For first occurrence of the primary endpoint [myocardial infarction (MI) or coronary heart disease (CHD) death] the hazard ratio (HR) and confidence intervals (Cox proportional hazards model) was 2.5 (1.2, 5.3) p=.02 in diabetic carriers of Thr-54 versus carriers without diabetes or fasting glucose >7 mmol/L. For the expanded endpoint (stroke, MI or CHD death), the corresponding HR was 3.0 (1.4, 5.4) p=.0003 and for the stroke alone the corresponding HR was 3.5 (1.4-8.9) p=.01. The higher cumulative incidence of the expanded endpoint in diabetic participants carrying the FABP2 polymorphism versus non-diabetic carriers was consistently present throughout the 5 years of the study (p=.0002). We conclude that based on the VA-HIT data, the Thr-54 polymorphism of the FABP2 gene is associated with a 2-3.5-fold increase in cardiovascular risk in dyslipidemic men with diabetes compared to their non-diabetic counterparts.
Atherosclerosis 2007 Sep
PMID:Codon 54 polymorphism of the fatty acid binding protein (FABP) 2 gene is associated with increased cardiovascular risk in the dyslipidemic diabetic participants of the Veterans Affairs HDL intervention trial (VA-HIT). 1694 73

The liver X receptors (LXRalpha and LXRbeta), ligand-activated transcription factors, belong to the superfamily of nuclear hormone receptors and have been shown to play a major role in atherosclerosis by modulating cholesterol and triglyceride metabolism. In this report, we describe a novel LXR target, the adipocyte fatty acid binding protein (aP2), which plays an important role in fatty acid metabolism, adipocyte differentiation and atherosclerosis. While LXR agonists induce aP2 mRNA expression in human monocytes (THP-1 cells) and macrophages in a time- and concentration-dependent manner, they have no effect on aP2 expression in human adipocytes. The increase in aP2 mRNA level was additive when THP-1 cells were treated with LXR and PPARgamma agonists. Also, an RXR agonist induced aP2 expression in these cells. While no additive effect was observed with LXR and RXR agonists, additive effects were observed with RXR and PPARgamma agonists. GW9662, a potent PPARgamma antagonist, inhibited PPARgamma-induced aP2 expression without affecting LXR-mediated aP2 expression indicating the induction is mediated directly through LXR activation. Analysis of human aP2 promoter revealed a potential LXR response element (LXRE). Gel shift data showed that the LXRalpha/RXRalpha heterodimer bound to the LXRE motif in aP2 promoter in vitro in a sequence-specific manner. Deletion and mutation analyses of the proximal aP2 promoter confirm that this is a functional LXRE. These data indicate for the first time that human macrophage aP2 promoter is a direct target for the regulation by LXR/RXR heterodimers.
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PMID:Adipocyte fatty acid-binding protein (aP2), a newly identified LXR target gene, is induced by LXR agonists in human THP-1 cells. 1739 33

Numerous studies have demonstrated that high blood pressure substantially increases the risk of microvascular and macrovascular complications in patients with type 2 diabetes mellitus (T2DM). Currently, we found that serum resistin, an adipocyte- and monocyte-derived cytokine, was positively correlated with several components of the metabolic syndrome, including hypertension in T2DM. To investigate the association of resistin with an etiologic difference among subjects with hypertension with T2DM, hypertension without T2DM, and normotensive T2DM, we analyzed 210 subjects, including 91 with hypertension with T2DM, 55 with hypertension without T2DM, and 64 with normotensive T2DM. Serum resistin level was higher in subjects with hypertension with T2DM, followed by subjects with normotensive T2DM and hypertension without T2DM, irrespective of antihypertensive treatment status (20.9+/-17.6 and 14.0+/-8.9 versus 11.2+/-7.6 ng/mL, respectively; P<0.01). Simple regression analysis revealed that resistin positively correlated with blood pressure (systolic blood pressure: r=0.29, P<0.01; diastolic blood pressure: r=0.21, P<0.05) and intima-media thickness (r=0.27; P<0.05) in patients with T2DM but not in subjects with hypertension without T2DM. Multiple regression analysis, adjusted for age, gender, body mass index, fasting glucose, high-density lipoprotein cholesterol, white blood cell counts, and glomerular filtration rate, further revealed that resistin was an independent factor for high blood pressure in patients with T2DM (P<0.05). In vitro gene expression analysis in human coronary endothelial cells revealed that resistin induced fatty acid binding protein, a key molecule of insulin resistance, diabetes, and atherosclerosis. These results suggest that hyperresistinemia would contribute to the pathogenesis of hypertension in patients with T2DM, significantly linked to vascular complications and cardiovascular events.
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PMID:Hyperresistinemia is associated with coexistence of hypertension and type 2 diabetes. 1818 Mar 99

The link between inflammation and the development of insulin resistance, type 2 diabetes, and atherosclerosis has been uncovered in the past decade. Although the molecular mechanisms underlying the co-occurrence of these metabolic and inflammatory diseases are not fully understood, several molecular players, integrating stress and inflammatory responses with metabolic homeostasis, were discovered recently. One of these molecular integration sites is through the action of cytosolic lipid chaperones or fatty acid binding proteins (FABPs), which are common to adipocytes and macrophages. Furthermore, studies in a variety of genetic models demonstrated that the FABPs aP2 and mal1 are critical mediators of many components of metabolic syndrome in mice. These exciting findings raise the possibility that FABPs represent desirable therapeutic targets for metabolic syndrome. In this review, we describe the findings demonstrating FABP's role in metabolic and inflammatory diseases and highlight recent advances in understanding the mechanisms of FABP function at the cellular and molecular level.
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PMID:Adipocyte/macrophage fatty acid binding proteins in metabolic syndrome. 1824 17

In the second part of the review, functional polymorphisms of some other lipid-related genes are considered, with a special emphasis on genetic variability of the fatty acid binding protein, lipoprotein lipase, hepatic lipase, and PPARs. Gene polymorphisms can profoundly influence metabolic responses to various dietary factors, e.g. effects of a special diet; on the other hand, dietary habits have modulatory effects on the expression of specific genotypes. Atherosclerosis and cardiovascular disease develop as a result of negative nutritional factors and individual genetic predisposition. A better comprehension of complex gene-gene and gene-environment interactions involved in cardiovascular risk could contribute to new preventive and therapeutic methods.
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PMID:[Gene-diet interactions in atherogenic dyslipidemias (part 2)]. 1825 2

Adipocyte/macrophage fatty acid binding protein (A-FABP) has been shown to be closely associated with metabolic syndrome, obesity and development of atherosclerosis. Moreover, A-FABP has been recently suggested as a potential therapeutic target of these abnormalities in animal models. The present review aims to summarize current knowledge on A-FABP functions and regulations both in animal models and humans, since the role of A-FABP in human physiology and disease has not been presently clarified.
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PMID:Fatty acid binding proteins in adipose tissue: a promising link between metabolic syndrome and atherosclerosis? 1897 52

Synthesis of nitric oxide (NO) can be blocked by inhibition of nitric oxide synthase (NOS) active site with guanidino-substituted analogues of l-arginine such as asymmetric dimethylarginine (ADMA). There is growing evidence that elevation of serum ADMA levels play a role in the progression of atherosclerosis and chronic kidney disease (CKD) in high-risk patients. Further, dyslipidemia contributes to cardiorenal disease as well. However, effects of ezetimibe, a specific inhibitor of cholesterol absorption and widely used drug for the treatment of dyslipidemia, on serum ADMA levels and renal injury remain unknown. In this study, we examined whether ezetimibe treatment decreased serum levels of ADMA, proteinuria and urinary excretion levels of 8-hydroxydeoxyguanosine (8-OHdG) and l-fatty acid binding protein (l-FABP), markers of oxidative stress and tubular injury, respectively and investigated their relationships in 10 non-diabetic CKD patients with dyslipidemia. Ezetimibe treatment (10mg/day) for 6 months significantly decreased circulating levels of LDL-cholesterol, triglycerides and ADMA, while it increased HDL-cholesterol levels. Further, ezetimibe treatment significantly reduced urinary excretion levels of protein, l-FABP and 8-OHdG. In univariate analyses, serum ADMA levels were correlated with urinary protein, l-FABP and 8-OHdG levels. In multiple stepwise regression analysis, proteinuria was independently correlated with ADMA. Our present study demonstrated for the first time that ezetimibe decreased serum ADMA levels and improved renal injury in non-diabetic CKD patients with dyslipidemia in a cholesterol-independent manner. Ezetimibe may have pleiotropic actions, that is, ADMA-lowering and anti-oxidative effects, that could contribute to renoprotective properties of this lipid-lowering agent.
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PMID:Ezetimibe decreases serum levels of asymmetric dimethylarginine (ADMA) and ameliorates renal injury in non-diabetic chronic kidney disease patients in a cholesterol-independent manner. 1940 91

We compared the gene expression of inflammatory and other proteins by real-time quantitative polymerase chain reaction in epicardial, substernal (mediastinal) and subcutaneous sternal, upper abdominal, and leg fat from coronary bypass patients and omental (visceral) fat from extremely obese women undergoing bariatric surgery. We hypothesized that (1) epicardial fat would exhibit higher expression of inflammatory messenger RNAs (mRNAs) than substernal and subcutaneous fat and (2) epicardial mRNAs would be similar to those in omental fat. Epicardial fat was clearly different from substernal fat because there was a far higher expression of haptoglobin, prostaglandin D(2) synthase, nerve growth factor beta, the soluble vascular endothelial growth factor receptor (FLT1), and alpha1 glycoprotein but not of inflammatory adipokines such as monocyte chemoattractant protein-1, interleukin (IL)-8, IL-1beta, tumor necrosis factor alpha, serum amyloid A, plasminogen activator inhibitor-1, or adiponectin despite underlying coronary atherosclerosis. However, the latter inflammatory adipokines as well as most other mRNAs were overexpressed in epicardial fat as compared with the subcutaneous depots except for IL-8, fatty acid binding protein 4, the angiotensin II receptor 1, IL-6, and superoxide dismutase-2. Relative to omental fat, about one third of the genes were expressed at the same levels, whereas monocyte chemoattractant protein-1, cyclooxygenase-2, plasminogen activator inhibitor-1, IL-1beta, and IL-6 were expressed at far lower levels in epicardial fat. In conclusion, epicardial fat does not appear to be a potentially more important source of inflammatory adipokines than substernal mediastinal fat. Furthermore, the expression of inflammatory cytokines such as IL-6 and IL-1beta is actually higher in omental fat from obese women without coronary atherosclerosis. The data do not support the hypothesis that most of the inflammatory adipokines are expressed at high levels in epicardial fat of humans.
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PMID:Human epicardial adipokine messenger RNAs: comparisons of their expression in substernal, subcutaneous, and omental fat. 2011 10

Lipocalin-type prostaglandin (PG) D synthase is expressed in adipose tissues and involved in the regulation of glucose tolerance and atherosclerosis in type 2 diabetes. However, the physiological roles of PGD(2) in adipogenesis in vivo are not clear, as lipocalin-type prostaglandin D synthase can also act as a transporter for lipophilic molecules, such as retinoids. We generated transgenic (TG) mice overexpressing human hematopoietic PGDS (H-PGDS) and investigated the in vivo functions of PGD(2) in adipogenesis. PGD(2) production in white adipose tissue of H-PGDS TG mice was increased approximately seven-fold as compared with that in wild-type (WT) mice. With a high-fat diet, H-PGDS TG mice gained more body weight than WT mice. Serum leptin and insulin levels were increased in H-PGDS TG mice, and the triglyceride level was decreased by about 50% as compared with WT mice. Furthermore, in the white adipose tissue of H-PGDS TG mice, transcription levels of peroxisome proliferator-activated receptor gamma, fatty acid binding protein 4 and lipoprotein lipase were increased approximately two-fold to five-fold as compared with those of WT mice. Finally, H-PGDS TG mice showed clear hypoglycemia after insulin clamp. These results indicate that TG mice overexpressing H-PGDS abundantly produced PGD(2) in adipose tissues, resulting in pronounced adipogenesis and increased insulin sensitivity. The present study provides the first evidence that PGD(2) participates in the differentiation of adipocytes and in insulin sensitivity in vivo, and the H-PGDS TG mice could constitute a novel model mouse for diabetes studies.
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PMID:Pronounced adipogenesis and increased insulin sensitivity caused by overproduction of prostaglandin D2 in vivo. 2013 55

The endothelium mediates relaxations (dilatations) of the underlying vascular smooth muscle cells. The endothelium-dependent relaxations are due to the release of non-prostanoid vasodilator substances. The best characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO). The endothelial cells also release substances (endothelium-derived hyperpolarizing factor, EDHF) that cause hyperpolarization of the cell membrane of the underlying vascular smooth muscle. The release of EDRF from the endothelium can be mediated by both pertussis toxin-sensitive G(i) (alpha(2)-adrenergic activation, serotonin, thrombin) and insensitive G(q) (adenosine diphosphate, bradykinin) coupling proteins. The ability of the endothelial cell to release relaxing factors can be upregulated by impregnation with estrogens, exercise and antioxidants, and down-regulated by oxidative stress and increased presence of oxidized LDL. Following injury or apoptotic death, the endothelium regenerates. However, in regenerated endothelial cells, there is an early selective loss of the pertussis-toxin sensitive mechanisms of EDRF-release. Functional studies suggest that abnormal handling of LDL because of increased oxidative stress play a key role in this selective loss. Genomic analysis demonstrates the emergence of fatty acid binding protein-A (A-FBP) and metalloproteinase-7 (MMP7) in regenerated endothelial cells. The reduced release of NO resulting from the endothelial dysfunction in regenerated areas creates a locus minoris resistentiae which favors the occurrence of vasospasm and thrombosis as well as the initiation of atherosclerosis.
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PMID:Regeneration of the endothelium in vascular injury. 2068 86


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